Growing evidence suggests that inflammation may be a central mechanism behind the development of many obesity-related diseases that include the metabolic syndrome and diabetes. Inflammatory changes in obesity include the infiltration of fat tissue with inflammatory macrophages. Adipose tissue macrophages (ATMs) can perturb normal adipocyte function and are necessary and sufficient to generate systemic insulin resistance in mouse models of obesity. This proposal seeks to understand the mechanisms by which ATMs alter adipocyte function and contribute to insulin resistance. The candidate's goals are (1) to increase his proficiency in immunology, (2) to become adept at the assessment of metabolism in animal models of obesity, and (3) through achieving the first two goals, to become an independent investigator with expertise in the mechanisms by which obesity generates inflammation and how this impacts human disease. The career development plan includes interdisciplinary mentorship from an expert in the obesity and metabolism, co-mentorship from an expert in chemokine biology, and collaboration with specialists in inflammation and diabetes. Preliminary studies indicated that obesity induced a switch in ATM activation state from an anti- inflammatory alternatively (M2) activated state in lean mice to a pro-inflammatory (M1) activated state in obese mice. While M1 macrophages rendered adipocytes insulin resistant, IL-10 produced from M2 macrophages protected adipocytes from the negative effects of TNFalpha. Experiments will test the hypothesis that IL-10 can prevent inflammatory changes in adipose tissue induced by obesity. The research plan will (1) assess the mechanisms by which IL-10 promotes normal adipocyte function, (2) assess the suppressive effects of IL-10 on ATM accumulation and activation in obese mice, and (3) test the hypothesis that IL-10 overexpression in macrophages will prevent adipose tissue inflammation and improve insulin sensitivity in obese mice. At the end of the funding period, the candidate expects to apply for independent funding based on his findings to further dissect the inflammatory changes caused by obesity in humans and mice. Relevance: This proposal examines the hypothesis that insulin resistance in obese mice can be prevented by blocking the inflammatory activation of macrophages in fat tissue. This will advance our understanding of the relationship between obesity, inflammation, and Type 2 Diabetes in humans.